The aim of this study was to examine basal ganglia volumes and regional cerebral blood flow in asymptomatic subjects at-risk for Huntington's disease (HO) who had undergone genetic testing. We determined which measures were the best "markers" for the presence of the mutation and for the onset of symptoms. Twenty subjects who were HD gene mutation-positive and 24 Huntington's disease gene mutation-negative participants, all of whom had a parent with genetically confirmed Huntington's disease, and were therefore 50% at-risk for inheriting the HD gene mutation, were included in the study. To evaluate basal ganglia structure and function, MRI and single photon emission computed tomography (SPECT) were used. Quantitative measures of regional volumes and relative measures of regional perfusion were calculated. SPECT and MRI scans were co-registered so that MRI anatomy could be used accurately to place SPECT regions. Estimated years-to-onset in the mutation-positive subjects was calculated based on a previously-described regression formula that included gene (CAG)~ repeat length and age of disease onset in the affected parent. Changes in imaging measures in relation to estimated yearsAo-onset were assessed. The imaging measure that was most affected in mutation-positive subjects was putamen volume. This was also the measure that correlated most strongly with approaching onset. In subjects >7 years from estimated onset age, putamen volume was similar to that of the mutation-negative subjects. However, in subjects s6 years from estimated onset age, there were dramatic reductions in putamen volume, resulting in >90% discrimination from both the farArom-onset and the mutation-negative subjects. Caudate volume and bicaudate ratio also showed a significantdecline in the close-to-onset subjects, although to a lesserdegree than putamen volume reductions. Furthermore, SPECT basal ganglia perfusion deficits were observed in mutation-positive subjects Imaging markers of neuropathological decline preceding clinical onset are important for assessing the effects of treatments aimed at slowing the course of HO. The current study suggests that quantitative assessment of basal ganglia may provide a means to track early signs of decline in individuals with the HO gene mutation prior to clinical onset.